ENG Technology Link Accell™ Bone Matrix (ABM) and Demineralized Bone Matrix (DBM) Figure 1: Particulate DBM Figure 2: Dispersed DBM 40x Figure 3: Particulate DBM (40x) Because we are committed to limiting uncertainty, we continuously develop new biologic technologies to complete the Integra biologic product line. The Difference between ABM and DBM Integra’s Accell™ Demineralized Bone Matrix is the next generation bone grafting product which advance standard allograft bone technology to the next level. The Accell™ family contains a proprietary form of processed allograft bone which is unique to DBM-based products. This proprietary form of DBM provides for early accessibility to bioactive bone proteins including bone morphogenetic proteins (BMPs) and other associated growth factors essential to the osteogenic process. The early accessibility to these bone proteins differentiates the Accell™ product family from standard DBM-based bone grafting products. Bone consists of primarily of Type-I collagen, mineral, and several naturally occurring growth factors. In 1965, Urist et al., discovered that removal of the mineral component of bone resulted in a bone matrix with osteoinductive properties (the ability to induce the formation of new bone). Accordingly, the demineralization process used on ground bone particles to produce DBM-based bone grafts imparts osteoinductivity by effectively “unshielding” the underlying bone matrix which contains the bioactive proteins. Standard demineralized bone matrix (DBM)-based products are composed primarily of particles of demineralized bone. After implantation, the osteoinductive process begins when enzymemediated digestion of these dense DBM particles effectively liberates natural bioactive proteins from the bone matrix. 40x Figure 4: Dispersed DBM (40x) The diffusion of natural bioactive proteins aids in the recruitment of cells to the bone defect where they can then differentiate into osteoblasts capable of forming new bone. The osteoinductive potential of DBM-based products is, therefore, attributable not only to the existence of specific BMPs and other associated growth factors contained within DBM, but also to the cellular accessibility to these osteoinductive proteins. Because time is required to fully digest DBM following implantation in bone defects, a novel processing technique was developed as a mean to further increase the accessibility to the critical components of bone matrix. To further increase the accessibility to natural bioactive bone proteins, Accell™ Demineralized Bone Matrix contains two forms of DBM; a standard form of “particulate-DBM” and a proprietary form of “dispersed-DBM.” Using the Accell™ process, particulate-DBM is converted into a dispersed form which increases the early availability of the bioactive proteins. In Accell™ Demineralized Bone Matrix it is the combination of both particulate — DBM and dispersed — DBM which makes the design distinct and more advanced among DBM — based bone graft products. Products for sale in Europe, Middle-East and Africa only Technology Link Accell™ Bone Matrix (ABM) and Demineralized Bone Matrix (DBM) The combination of a highly dispersed form of DBM and particulate-DBM provides the unique advantage to Accell™ Demineralized Bone Matrix over traditional DBM-based bone products limited to utilizing only particulate forms of DBM in the formulation. In a study presented at the 52nd Annual Meeting of the Orthopaedic Research Society, it was shown that dispersedDBM produced from the Accell™ process contains a natural array of growth factors, including BMP-2, 4, 7, and TGF-ß1. Apart from the presence of these growth factors, it is the structural differences between dispersed and particulate-DBM that make the Accell™ technology unique (see Figures 1– 5). Figure 5: Dispersed DBM In a more recent study presented at the 55th Annual Meeting of the Orthopaedic Research Society, it was shown that in the presence of collagenase (an enzyme used to mimic in vivo degradation of DBM), it takes approximately 5 days for particulate-DBM to reach maximal accessibility to the bioactive bone proteins. In contrast, dispersed-DBM (with or without collagenase) was shown to reach maximal accessibility to the bioactive bone proteins within 4 hours of hydration. Figure 7: Combination of Dispersed and Particulate DBM (40x) As shown in Figure 8, the accessibility to BMP-2 occurs rapidly in dispersed-DBM whereas the accessibility to BMP-2 in particulate-DBM is slower and sustained over a longer period of time. These results are anticipated considering the inherent dense nature of DBM particles in contrast to the highly porous nature of the dispersed form (see Figures 3 and 4). Figure 6: Particulate DBM The differences in the structural organization of Type-I collagen and natural bioactive bone proteins in particulate and dispersed forms of DBM is graphically represented in Figures 6 and 7. The in-vivo component of this study demonstrated that Accell™ technology was as effective as iliac crest bone graft in generating new bone in a challenging spine fusion model. Accell™ w/o collagenase 18.00 DBM w/ collagenase 16.00 DBM w/o collagenase BMP-2 Conteny (ng/g) 14.00 References 1. M. R. Urist Formation by Autoinduction. Science 150: 893-899, 1965 12.00 10.00 8.00 6.00 2. R.Fuhrmann, A. Wagner, J. Anders Tissue repair composition and methods for their manufacture and use. US Patent No. 7,132,110. 4.00 2.00 0.00 3. Evaluation of Next Generation DBM Putty in a Posterolateral Spinal Fusion Model. Paper # 1834, 55th Annual Meeting of the Orthopaedic Research Society (2009). Integra LifeSciences Services (France) SAS Sales & Marketing EMEA Immeuble Séquoia 2 97 allée Alexandre Borodine Parc technologique de la Porte des Alpes 69800 Saint Priest FRANCE Phone +33 (0)4 37 47 59 00 Fax +33 (0)4 37 47 59 99 emea.info@integralife.com integralife.eu www.integraorthobiologics.com 0 20 40 60 80 100 120 Time (hrs) Figure 8: Accessibility to a Specific Bioactive Bone Protein, Dispersed vs. Particulate DBM Distributed by IsoTis Orthobiologics 2 Good Year Suite A Irvine, CA 92618 United States of America +1 (949) 595 8710 fax: +1 949 595 8711 97 ©2011 Integra LifeSciences Corporation. All rights reserved. ILS 07-06-001-01-11 PRODUCTS FOR SALE IN EUROPE, MIDDLE-EAST and AFRICA ONLY Availability of these products might vary from a given country or region to another, as a result of specific local regulatory approval or clearance requirements for sale in such country or region. Always refer to the appropriate instructions for use for complete clinical instructions. Non contractual document. The manufacturer reserves the right, without prior notice, to modify the products in order to improve their quality. WARNING: Applicable laws restrict these products to sale by or on the order of a physician. Accell, Integra and the Integra logo are trademarks of Integra LifeSciences Corporation or its subsidiaries. All the references numbers mentioned on this document are CE marked according to European council directive 93/42/EEC on medical devices, unless specifically identified as “NOT CE MARKED.”